Pregabalin-containing, high swellable, sustained-release triple layer tablet

ABSTRACT

Disclosed a pregabalin-containing, high swellable, oral sustained-release triple layer tablet suitable for administration once daily.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national phase application of PCT Application No.PCT/KR2017/003378, filed on Mar. 29, 2017, which claims the benefit andpriority to Korean Patent Application No. 10-2017-0014591, filed Feb. 1,2017. The entire disclosures of the applications identified in thisparagraph are incorporated herein by references.

TECHNICAL FIELD

The present invention relates to a sustained-release triple layer tabletcontaining pregabalin. More specifically, the present invention relatesto a triple layer tablet consisting of an upper layer and a lower layercomprising pregabalin or a pharmaceutically acceptable salt thereof anda swellable polymer; and an intermediate layer comprising pregabalin ora pharmaceutically acceptable salt thereof and a medium transfer agent.The triple layer tablet of the present invention consists of an upperlayer and a lower layer comprising a swellable polymer, and anintermediate layer positioned therebetween.

According to the present invention, an aqueous medium (for example,water, gastric fluid, intestinal fluid, etc.) is effectively deliveredto the swellable polymer of the upper layer and the lower layer throughthe medium transfer agent of the intermediate layer, thereby furtherincreasing the swellability. The preparation according to the presentinvention enables a drug to remain in the gastrointestinal tract formore long time. Thereby, the preparation can improve the absorptionefficiency of the drug in the upper portion of the gastrointestinaltract, and control the drug to be released continuously. As such, thepreparation according to the present invention is a gastro-retentivesustained-release preparation, and thus this preparation is suitable foradministration once daily.

BACKGROUND

Pregabalin is an analog of γ-aminobutyric acid (Gamma-aminobutyric acid,GABA). Its chemical name is (S)-3-(aminomethyl)-5-methylhexanoic acid,its molecular equation is C₈H₁₇NO₂, and its molecular weight is 159.23.

U.S. Pat. No. 5,563,175 discloses that γ-aminobutyric acid is useful asantiseizure therapy for central nervous system disorders such asepilepsy, Huntington's chorea, cerebral ischemia, Parkinson's disease,tardive dyskinesia, and the like, and U.S. Pat. No. RE 41,920 disclosesthat isobutylgaba, glutamic acid and γ-aminobutyric acid, which arederivatives of isobutylgaba, are effective in pain therapy againsthyperalgesic and allodynic actions.

Pregabalin is a white or pale yellow crystalline powder, which has awater-soluble property. Pregabalin is bonded to an alpha-2-delta (α2δ)subunit of a calcium channel in the central nerve, and is involved inthe regulation of neurotransmitter(γ-aminobutyric acid) activity, andthis is used for the treatment of peripheral and central neuropathicpain, epilepsy, fibromyalgia, etc. When pregabalin is orallyadministered with between 1 and 600 mg, the absorption amount isdose-dependent, the maximum blood level arrival time (Tmax) is between0.8 to 1.2 hours, and the half-life of a drug is between 5.2 to 6.6hours. At present, pregabalin has been commercially available in oralcapsule products (product name: Lyrica Capsule, Pfizer) that can beadministered twice daily at a daily dose of from 150 mg up to 600 mg atmaximum, and this can be used only as immediate release formulations.

However, drugs that are administered twice daily or three times dailyare inconvenience for patients who take the drugs. Compliance to elderlypatients or patients who take drugs for a long time is greatly reduced.

Since pregabalin can be used only in formulations that can beadministered twice daily, this is inconvenient in terms of compliance.

If the drug administration method is changed to be administered oncedaily through the preparation development, there are followingadvantages that: compliance to patients will be greatly improved; drugconcentration in blood can be maintained constantly, thereby reducing orpreventing undesired dose-dependent side effects; and drug efficacy canbe maintained continuously.

Especially, it has been known that for first administration, pregabalincan be administered twice daily and its dose can be gradually increasedfrom 75 mg for one time up to 600 mg for day at maximum at an intervalof 7 days, and the arrival time to a drug steady-state takes 24 to 48hours after first intake.

Herein, if the dose is gradually increased while observing a drugreaction shown when taking a drug with accurately complying with thedose having high compliance through the method such as an administrationonce daily, more accurate final dose can be determined in terms ofsafety and efficiency. This is because, if compliance is low, the doseis not accurate, and thus the final dose which is determined byincreasing the dose while observing the drug reaction may be inaccurate.

According to existing clinical studies, it has been known thatpregabalin is not absorbed homogeneously in the gastrointestinal tract,and that most of drugs are absorbed by an L-amino acid transporter inthe upper portion of the gastrointestinal tract. Therefore, theabsorption occurs mainly in the small intestine and the ascending colon,and if the drugs pass through the hepatic flexure, the drugs are hardlyabsorbed.

It has been known that conventional sustained-release tablets passthrough the hepatic flexure at about 6 hours after the administration.Thus, in the case of developing sustained-release tablets containingpregabalin, the tablets will pass through the hepatic flexure at about 6hours after the administration. However, since pregabalin is hardlyabsorbed in the hepatic flexure, the drug release of the generalpregabalin-containing sustained-release tablets after 6 hours is notclinically significant. As such, since there is a limitation of timewhen pregabalin is absorbed in the body after the administration, thereis a problem in developing formulations that can be administered oncedaily.

DETAILED DESCRIPTION Summary of Invention

There is a problem that pregabalin cannot have pharmacokineticproperties suitable for administration once daily, because there is alimitation of site where the drug is absorbed in the gastrointestinaltract and, thus, there is a limitation of absorption time after theadministration.

Generally, in order to develop formulations suitable for administrationonce daily, the drug concentration effective in the body should bemaintained for 24 hours. Thus, the drug absorption time of pregabalinshould be increased by extending the time until pregabalin passesthrough the hepatic flexure which is the site where the absorption ofpregabalin is limited.

The present invention aims to prepare a pregabalin-containing, highswellable, oral sustained-release triple layer tablet, using agastroretentive drug delivery system, in order to solve the problems.

Accordingly, the present invention aims to provide apregabalin-containing sustained-release preparation for oraladministration once daily, having pharmacokinetic properties of reducingside effect while increasing compliance and extending the efficacy timeduration, as compared to conventional pregabalin-containing preparationsfor oral administration twice daily.

Technical Solution

The present invention relates to a sustained-release triple layer tabletcontaining pregabalin. More specifically, the present invention relatesto a pregabalin-containing, sustained-release triple layer tablet,comprising an upper layer and a lower layer comprising a swellablepolymer; and an intermediate layer comprising a medium transfer agent,wherein the triple layer tablet swells to at least 250% of its originalvolume at two hours after the tablet is in contact with an aqueousmedium.

In addition, the present invention relates to a triple layer tabletconsisting of an upper layer and a lower layer comprising pregabalin ora pharmaceutically acceptable salt thereof and a swellable polymer; andan intermediate layer comprising pregabalin or a pharmaceuticallyacceptable salt thereof and a medium transfer agent, wherein the triplelayer tablet swells to at least 250% of the original volume at two hoursafter the tablet is contact with an aqueous medium.

The triple layer tablet of the present invention consists of an upperlayer and a lower layer comprising a swellable polymer, and anintermediate layer positioned therebetween, wherein the triple layertablet swells to at least 250% of its original volume at two hours afterthe tablet is contact with an aqueous medium.

According to the present invention, the aqueous medium is effectivelydelivered to the swellable polymer of the upper layer and the lowerlayer through the medium transfer agent of the intermediate layer,thereby further increasing the swellability. The preparation accordingto the present invention enables a drug to remain in thegastrointestinal tract for more long time. Thereby, the preparation canimprove the absorption efficiency of the drug in the uppergastrointestinal tract, and control the drug to be releasedcontinuously. As such, the preparation according to the presentinvention is a gastro-retentive sustained-release preparation, and thusthe preparation is suitable for administration once daily.

Effect of Invention

As for drugs such as pregabalin that are mainly absorbed in the upperportion of the gastrointestinal tract, a preparation suitable foradministration once daily was developed by applying thesustained-release preparation technology of adjusting the drug releaserate, and the gastro-retentive drug delivery system at the same time.

In the present invention, the swellable polymer is separated into theupper layer and the lower layer, and the medium transfer agent ispositioned between the upper layer and the lower layer, so that thelarge amount of aqueous medium can be rapidly delivered to the swellablepolymer. Thus, the triple layer tablet of the present invention canswell to at least 250% of its original volume at two hours after thetablet is contact with the aqueous medium, and thereby improvedswellability can be obtained as compared to tablets in single matrixforms and the size change of the tablet is larger than that in tabletsin single matrix forms.

As such, tablets with increased size cannot pass through the pylorus andremain in the stomach for a longer period.

Therefore, according to the present invention, the extension of thegastric residence time and the improvement of drug absorption resultingtherefrom are possible, thereby providing a sustained-release triplelayer tablet that can be administered once daily.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a graph comparing the volume changes in the swelling test ofthe pregabalin-containing oral sustained-release triple layer tabletsprepared in Examples 1 to 4.

FIG. 2 is a graph comparing the volume changes in the swelling test ofthe pregabalin-containing oral sustained-release triple layer tabletsprepared in Examples 5 to 7.

FIG. 3 is a graph showing the pharmacokinetic test results obtained byadministering the tablet of Example 8 once and control agents (Lyrica®capsule) twice in beagle dogs, respectively.

Best Mode For Embodiment Of Invention

The present invention relates to a sustained-release triple layer tabletcontaining pregabalin. More specifically, the present invention relatesto a triple layer tablet consisting of an upper layer and a lower layercomprising pregabalin or a pharmaceutically acceptable salt thereof anda swellable polymer; and an intermediate layer comprising pregabalin ora pharmaceutically acceptable salt thereof and a medium transfer agent,wherein the triple layer tablet swells to at least 250% of its originalvolume at two hours after the tablet is contact with an aqueous medium.The triple layer tablet of the present invention consists of an upperlayer and a lower layer comprising a swellable polymer, and anintermediate layer positioned therebetween.

According to the present invention, the aqueous medium is effectivelydelivered to the swellable polymer of the upper layer and the lowerlayer through the medium transfer agent of the intermediate layer, sothat the triple layer tablet swells to at least 250% of its originalvolume at two hours after the tablet is contact with the aqueous medium,thereby further increasing swellability. The preparation according tothe present invention enables a drug to remain in the gastrointestinaltract for more long time. Thereby, the preparation can improve theabsorption efficiency of the drug in the upper gastrointestinal tract,and control the drug to be released continuously. As such, thepreparation according to the present invention is a gastro-retentivesustained-release preparation, so this preparation is suitable foradministration once daily.

The oral sustained-release triple layer tablet according to the presentinvention may have a therapeutically effective amount of pregabalin perunit dosage form.

The triple layer tablet of the present invention consists of threelayers, and specifically, consists of an upper layer and a lower layercomprising a swellable polymer, and an intermediate layer comprising amedium transfer agent therebetween. However, depending on cases, thetablet can be prepared as a multilayer tablets consisting of three ormore layers comprising said three layers.

When the triple layer tablet of the present invention is in contact withthe aqueous medium, the medium transfer agent present in theintermediate layer introduces the aqueous medium into the tablet, andthen delivers the aqueous medium to the swellable polymer present in theupper layer and the lower layer, thereby improving the swellability ofthe upper layer and the lower layer, so that the tablet swells to atleast 250% of its original volume at two hours after the tablet is incontact with the aqueous medium. Such preparation enables a drug toremain in the gastrointestinal tract for more long time, therebyimproving the absorption efficiency of the drug in the upper portion ofthe gastrointestinal tract and controlling the drug to be releasedcontinuously, so as to provide an oral sustained-release preparationsuitable for administration once daily.

The tablet rapidly swelled by the intermediate layer comprising themedium transfer agent preferably has the size of 12 mm or more, which isthe average diameter of the adult pylorus, in order to prevent thetablet from being rapidly released in the stomach. Herein, depending onthe shape that can influence when the tablet passes through the pylorus,in the case of round tablets, the size of the tablet refers to adiameter, and in the case of oval or oblong tablets, the size of thetablet refers to a diameter of the minor axis of the tablet.

Although the gastric emptying time of drugs may vary depending onvarious conditions such as intake of food, etc., it has been known thatorally administered formulations generally pass through the stomach intwo hours in the fasted state. Thus, the administered formulation shouldbe swelled to be big within two hours, which is difficult to passthrough the pylorus and to this end, the volume increase rate within twohours should be at least 250% (that is, swelling to a volume of 2.5times larger than its original tablet volume), preferably, at least 300%(that is, swelling to a volume of 3 times larger than its originaltablet volume). In addition, in order to implement the drug releasespeed suitable for administration once daily, the volume increase rateup to 6 hours should be at least 250% (that is, swelling to a volume of2.5 times larger than its original tablet volume), preferably, at least300% (that is, swelling to a volume of 3 times larger than its originaltablet volume), and the volume increase rate up to 6 hours should bepreferably equal to or more than the volume increase rate within 2hours, and should not be reduced than the volume increase rate within 2hours.

In addition, in the multilayer tablet of the present invention, thelength of the minor axis of the tablet at two hours after the tablet isin contact with the aqueous medium is 12 mm or more, and preferably, thelength of the minor axis of the tablet for 2 hours to 6 hours after thetablet is in contact with the aqueous medium is at least 12 mm.

In the tablet of the present invention, the upper layer and the lowerlayer comprise a swellable polymer. Pregabalin, which is an activeingredient, may be comprised in any one of the upper layer and the lowerlayer or in both of them. The composition or amount of the upper layerand the lower layer may be identical to or different from each other.

The triple layer tablet of the present invention may have variousphysical forms such as round, oval, oblong, triangle, etc. Inconsideration of convenience of intake, the smaller size of the preparedtablet is better; however, since the tablet should be rapidly swelled toa size that does not pass through the pylorus after administration ofthe tablet, after two hours from the swelling test, the diameter ofround tablets (or in the case of tablets in different forms, thediameter of the shortest minor axis among the cross sections of thetablets) is preferably 12 mm or more.

The triple layer tablet of the present invention comprises a swellablepolymer in the upper layer and the lower layer and a medium transferagent in the intermediate layer, and pregabalin, which is an activeingredient, may be comprised in all of the upper layer, the intermediatelayer and the lower layer, or comprised only in the intermediate layeror in only the upper layer and the lower layer, or in any one of theupper layer and the lower layer depending on cases, in order to exhibita release speed or a release pattern suitable for administration oncedaily.

When the triple layer tablet is in contact with the aqueous medium, themedium is penetrated into all of the upper layer, the intermediate layerand the lower layer. The aqueous medium is rapidly penetrated into thecenter of the tablet through particularly, the medium transfer agentcomprised in the intermediate layer, and the aqueous medium penetratedinto the intermediate layer of the tablet is rapidly delivered to theupper layer and the lower layer, so that the tablet swells fast to thetargeted size. The upper layer and the lower layer rapidly swelled assuch swell also to the side of the intermediate layer so that they canbe attached to each other. Thus, the size of the tablet swells not onlyto the up and down longitudinal direction but also to the transversedirection when viewed from the side direction. Through such process, therelease speed of pregabalin can be adjusted to be suitable foradministration once daily.

In the triple layer tablet of the present invention, the intermediatelayer comprises pregabalin and a medium transfer agent. The intermediatelayer does not contain a polymer substance, except for a binder usedduring the granulation preparation process, for rapid delivery ofwater-solution medium. Thus, the intermediate layer in the triple layertablet of the present invention is appropriately disintegrated within 30minutes which are the reference time for general release preparations,in the case of conducting a test only for the intermediate layer, exceptfor the upper layer and the lower layer, according to the disintegrationtest method among the Korean Pharmacopoeia Disintegration Test Methods.

The medium transfer agent serves, as implied from its name, as providinga route through which water can be rapidly absorbed into the preparationand delivering the absorbed water to the swellable polymer of the upperlayer and the lower layer when the triple layer tablet is in contactwith gastric fluid after intake or in contact with the aqueous mediumduring the dissolution test, thereby increasing the swelling speed ofthe tablet to increase the size of the triple layer tablet.

It was confirmed that the triple layer tablet of the present inventionswelled in such manner has greatly increased swelling speed and swellingmaintenance time as compared to general single layer tablets comprisinga swellable polymer and a medium transfer agent together.

In the present invention, the amount of the medium transfer agentcomprised in the intermediate layer of the triple layer tablet ispreferably 10% (w/w) to 70% (w/w), more preferably, 10% (w/w) to 50%(w/w), relative to the total amount of the swellable polymer comprisedin the upper layer and the lower layer.

As the medium transfer agent of the present invention, substances withgood solubility to water or substances which have wicking of inducingpenetration of medium even if its solubility is low are used aspharmaceutically acceptable excipients having high affinity with theaqueous medium.

As excipients having good solubility, excipients having solubilitydefined as “freely soluble” in the Korean Pharmacopoeia SolubilityStandard Table (for example, not less than 1 mL and not more than 10 mLof solvent is required to dissolve solute 1 g) are suitable. As suchexcipients, sugars (for example, dextrose, dextrate, dextrin, lactose,sucrose, glucose, mannitol, isomalt, xylitol, erythritol and sorbitol,etc.), polyvinylpyrrolidone, salts (for example, sodium chloride,magnesium chloride, sodium phosphate, etc.), organic acids (for example,fumaric acids, tartaric acid, etc.) or a mixture thereof can be used

Substances which have wicking of inducing penetration of an aqueousmedium have the hydrophilic property even though its solubility to wateris low and have roles as absorbing the aqueous medium and inducing suchthat the aqueous medium can be penetrated continuously. As excipientscorresponding thereto, starch (for example, corn starch, potato starch,pre-gelatinized starch, etc.), microcrystalline cellulose,low-substituted hydroxypropylcellulose or a mixture thereof can be used.

The upper layer, the lower layer and the intermediate layer in thetriple layer tablet of the present invention each may optionallycomprise a pharmaceutically acceptable binder. The binder is containedin the amount of less than 20% (w/w) relative to the weight of eachlayer in which the binder is comprised. The binder can be used forpreparing a granule containing a pharmaceutical active material and aswellable polymer, as needed. As the binders, polyvinylpyrrolidone,copovidone, low-viscosity hypromellose having a viscosity of 100 cps orless in an aqueous solution 2% (w/w) (at 20° C.) or a mixture thereofcan be used.

The triple layer tablet of the present invention may optionally compriseone or more lubricants that are required for the preparation processsteps including smooth mixing or tableting process in each layer. Thelubricants are comprised in the amount of less than 3% (w/w),preferably, in the range of 1% (w/w) to 3% (w/w), relative to the weightof each layer in which the lubricants are comprised. As the lubricants,talc, stearate or metal salt thereof (for example, calcium stearate,magnesium stearate, etc.), stearic esters (for example, polyoxyethylenestearate, glyceryl monostearate, glyceryl palmitostearate, etc.),glyceryl behenate, polyethylene glycol, benzoic acids or a mixturethereof can be used.

The swellable polymer comprised in the upper layer and the lower layerhas a swelling property when the tablet is in contact with an aqueousmedium.

In order for an oral sustained-release tablet suitable foradministration once daily to maintain the effective blood level evenafter 24 hours from the administration, a portion of the preparation inprogress of gelation is needed to remain in the gastrointestinal tractas long as possible for at least 6 to 8 hours, preferably for at least12 hours, after the administration.

As the swellable polymer comprised in the upper layer and the lowerlayer in the triple layer tablet of the present invention, polyethyleneglycol, hypromellose, hydroxypropylcellulose, carboxymethylcellulose,polyvinyl alcohol, carbomer, etc. can be used.

The swellable polymer can be used alone or a mixture of two or morekinds of the polymers can be used. Or, two or more kinds of polymermixtures, having properties suitable for the present invention, orcopolymers can be properly used for the present invention.

In addition, the swellable polymer that can be used in the preparationof the present invention preferably shows a high viscosity. For example,the viscosity in 2% (w/w) aqueous solution (25° C.) is preferably 400cps or more, and the viscosity in 1% (w/w) aqueous solution (25° C.) ismore preferably 2,000 cps or more.

The upper layer and the lower layer may further comprisepharmaceutically acceptable excipients, for example, diluents orfillers. The amount of the excipients may be in the range of 50% (w/w)or less, preferably, in the range of 40% (w/w) or less, relative to theweight of each layer. The excipients can increase the physical propertyof the triple layer tablet while providing the fluidity of granule andhardness improvement of the tablet in the mixing and tableting process.Representative examples of the excipients include sugars (for example,dextrose, dextrate, dextrin, lactose, sucrose, glucose, mannitol,isomalt, xylitol, erythritol and sorbitol, etc.), cellulose (forexample, crystalline cellulose, microcrystalline cellulose,microcrystalline cellulose silicide, low-substitutedhydroxypropylcellulose, etc.), starch (for example, corn starch, potatostarch, pre-gelatinized starch, etc.), salts (for example, sodiumchloride, calcium carbonate, calcium hydrogen phosphate, calciumphosphate, magnesium carbonate, etc.), organic acids (for example,fumaric acids, tartaric acid, etc.) or a mixture thereof.

Meanwhile, even if the triple layer tablet of the present invention doesnot comprise binders, diluents or fillers in the upper layer and thelower layer, the swellable polymer of the upper layer and the lowerlayer can swell by a medium transfer agent of the intermediate layer.

The oral sustained-release triple layer tablet of the present inventionthat swells to at least 250% of its original volume at two hours afterthe tablet is in contact with the aqueous medium can be prepared by amethod comprising:

(i) a step of preparing a tableting blend for an upper layer and a lowerlayer consisting of a mixture in which pregabalin or a pharmaceuticallyacceptable salt thereof and a swellable polymer are mixed, or granulesin which they are granulated;

(ii) a step of preparing a tableting blend for an intermediate layerconsisting of a mixture in which pregabalin or a pharmaceuticallyacceptable salt thereof and a medium transfer agent are mixed, orgranules in which they are granulated; and

(iii) a step of preparing a triple layer tablet by tableting the blendprepared at the step (i) and the blend prepared at the step (ii).

In the preparation method, the tableting blend prepared at the step (i)may further comprise excipients, binders or lubricants, and thetableting blend prepared at the step (ii) may also further comprisebinders or lubricants.

In addition, also at the step (iii), the tableting can be performed byfurther comprising lubricants.

The tableting blend prepared at the step (iii) is tableted according totypical methods. For example, the triple layer tablet of the presentinvention can be prepared by mixing the ingredient of each layer of theupper layer, intermediate layer and lower layer respectively using amixer and then direct-tableting it using a multilayer tableting machine.Or, the triple layer tablet of the present invention can be prepared bymixing the ingredient of each layer to prepare a granule respectivelyusing a high speed mixer, a fluidized-bed granulator or a rollercompressor, etc. and adding a lubricant to make it lubricated, and thentableting it using a multilayer tableting machine.

The sustained-release preparation of the present invention can beprepared in a multilayer tablet consisting of three or more layersdepending on cases.

EMBODIMENT OF THE INVENTION EXAMPLES

Hereinafter, the present invention will be explained in more detailthrough the following examples. However, the following examples are onlyto exemplify the present invention, and the scope of the presentinvention is not limited to the following examples.

Examples 1 to 8

According to the component ratio (unit: mg) of the following table,pregabalin and polyethylene oxide (product name: Polyox WSR, DowChemicals) as a mixture to be used in the upper layer and the lowerlayer were mixed and passed through 25 mesh sieve. Thereafter, thismixture was mixed with magnesium stearate that passed through 30 meshsieve.

In addition, pregabalin and the medium transfer agent as a mixture ofthe intermediate layer were mixed and passed through 25 mesh sieve.Thereafter, this mixture was mixed with magnesium stearate that passedthrough 30 mesh sieve.

The amount of each mixtures to be used in the upper layer, the lowerlayer and the intermediate layer was measured, and the oblong triplelayer tablets (Examples 1 to 8) were prepared using a triple layertableting machine or compressor.

TABLE 1 Compositions of Examples 1 to 4 (unit: mg) Example 1 Example 2Example 3 Example 4 Upper layer pregabalin 45 120 60 60 polyethyleneoxide 150 250 200 200 (Polyox WSR 303) magnesium 3 5 4 4 stearateIntermediate layer pregabalin 60 60 30 30 lactose 70 dextrate 150tartaric acid 70 microcrystalline 70 cellulose magnesium 2 3 1 1stearate Lower layer pregabalin 45 120 60 60 polyethylene oxide 150 250200 200 (Polyox WSR 303) magnesium 3 5 4 4 stearate Total amount 528 963629 629

TABLE 2 Compositions of Examples 5 to 8 (unit: mg) Example 5 Example 6Example 7 Example 8 Upper layer pregabalin 60 75 60 60 polyethyleneoxide 150 300 150 (Polyox WSR 303) polyethylene oxide 200 (Polyox WSRN12K) magnesium 3 5 4 2 stearate Intermediate layer pregabalin 30 10 3030 dextrate 150 microcrystalline 70 cellulose hydroxypropyl 20methylcellulose mannitol 50 150 45 tartaric acid 30 magnesium 1 5 1 1stearate Lower layer pregabalin 60 75 60 60 polyethylene oxide 150 300150 (Polyox WSR 303) polyethylene oxide 200 (Polyox WSR N12K) magnesium3 5 4 2 stearate Total amount 527 1075 629 530

Test Example 1 Swelling Test

A tablet was put into a vessel containing 0.06N HCl 900 mL, and themixture was stirred at a rotation speed of 50 rpm using USP dissolutionmethod 2 (paddle). Then, the size of the tablet was measured usingcalipers over the time. The volume and volume increase rate of thetablet were calculated based on the following equation.*volume (mm³)=major axis (mm)×minor axis (mm)×height (mm)*volume increase rate (%)=(volume at the measured time/volume at 0 hour(that is, just before the test))×100(%)

TABLE 3 Time (hr) Example 1 2 3 4 5 6 7 8 0 major axis 14.0 19.9 18.118.0 15.0 19.9 18.0 16.1 (mm) minor axis 8.0 8.8 8.1 8.0 8.5 8.8 8.0 8.1(mm) Thickness 6.1 7.0 5.8 5.8 5.6 7.4 5.7 5.3 (mm) Volume 689.2 1229.4844.2 833.7 712.4 1300.4 823.7 686.8 (mm³) Volume 100.0 100.0 100.0100.0 100.0 100.0 100.0 100.0 increase rate (%) 2 major axis 23.9 24.624.8 28.5 19.8 24.8 24.0 20.7 (mm) minor axis 15.9 13.4 12.3 13.1 12.613.3 12.0 13.1 (mm) Thickness 11.3 11.9 9.1 10.6 9.9 13.0 10.7 9.9 (mm)Volume 4273.0 3922.5 2754.6 3959.4 2463.3 4283.4 3078.4 2678.1 (mm³)Volume 620.0 319.1 326.3 474.9 345.8 329.4 373.7 389.9 increase rate (%)6 major axis 28.6 28.4 28.8 33.5 22.3 30.3 27.5 24.8 (mm) minor axis18.1 14.3 14.3 16.4 12.5 14.5 13.4 16.7 (mm) Thickness 10.4 11.9 13.012.4 10.1 14.9 11.8 11.3 (mm) Volume 5349.1 4803.4 5348.2 6805.1 2814.66531.0 4350.8 4645.4 (mm³) Volume 776.1 390.7 633.6 816.2 494.7 502.2528.2 676.4 increase rate (%)

Referring to table 3, FIG. 1 and FIG. 2, it can be confirmed that inexamples 1 to 8, the volume increase rate at 2 hours are rapidlyincreased to 300% or more, and the volume increase rate at 6 hours areincreased more than the volume increase rate at 2 hours. In addition, itwas confirmed that the major axis and the minor axis of the tablet canbe maintained to 12 mn or more for 6 hours after swelling.

Test Example 2 Pharmacokinetic Test in Beagle Dogs

Pharmacokinetic test in beagle dogs was performed for the table ofExample 8 as the test drug and the commercially available Lyrica capsule75 mg as the control. About 11 kg of beagle dogs were divided intogroups of 8 dogs. A capsule as the control drug was administrated twiceat initial time and 10 hours later respectively. The tablet (test drug)of example 8 was administrated once daily. Blood was collected for 24hours after the first administration, and then the blood was analyzed tocalculate each pharmacokinetic parameter. The results are shown in thefollowing table 4.

TABLE 4 percentage (example/ Parameter Example 8 Reference drugreference drug) AUC_(24 hr)(μg · hr/mL) 169.87 162.40 1.05C_(max)(μg/mL) 13.34 15.75 0.85 T_(max)(hr) 5.9 10.7 (1^(st)peak: 0.9)

As the test results of table 4 and FIG. 3, it was confirmed that example8 in which the tablet was administered once daily has good absorptionrate and extent as compared to the control drug that was administeredtwice daily. Accordingly, it can be understood that according to thepreparation of the present invention, pregabalin can be administeredonce daily.

Industrial Applicability

The preparation of the present invention comprising pregabalin can beadministered once daily. Accordingly, the compliance can be greatlyimproved.

What is claimed is:
 1. A multilayer tablet comprising: an upper layerand a lower layer both comprising pregabalin or a pharmaceuticallyacceptable salt thereof and a swellable polymer; and an intermediatelayer comprising pregabalin and a medium transfer agent, theintermediate layer being positioned between the upper layer and thelower layer, wherein the tablet swells to at least 250% of its originalvolume at two hours after the tablet is in contact with an aqueousmedium and maintains the 250% of its original volume at 6 hours afterthe tablet is in contact with the aqueous medium, wherein the tablet isan oral sustained-release composition suitable for once dailyadministration, wherein an amount of pregabalin in the intermediatelayer is 6.25% to 40% of a total amount of pregabalin in the multilayertablet, and wherein an amount of pregabalin in the upper layer is 30% to46.88% of the total amount of pregabalin in the multilayer tablet. 2.The multilayer tablet according to claim 1, wherein the tablet has thelength of the minor axis of the tablet of 12 mm or more at two hoursafter the tablet is in contact with the aqueous medium.
 3. Themultilayer tablet according to claim 2, wherein the tablet has thelength of the minor axis of the tablet of 12 mm or more for 2 hours to 6hours after the tablet is in contact with the aqueous medium.
 4. Themultilayer tablet according to claim 1, wherein the tablet swells to atleast 300% of its original volume at two hours after the tablet is incontact with the aqueous medium.
 5. The multilayer tablet according toclaim 4, wherein the tablet swells to at least 300% of its originalvolume for 2 to 6 hours after the tablet is in contact with the aqueousmedium.
 6. The multilayer tablet according to claim 1, wherein themedium transfer agent has an ability of absorbing the aqueous medium anddelivering the aqueous medium to the upper layer and the low layer, andwherein the medium transfer agent is (i) an excipient having hydrophilicproperty or (ii) an excipient having a solubility that at most 10 mL ofwater is required to dissolve 1 g of the excipient.